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Radiation-induced lymphopenia: the main aspects to consider in immunotherapy trials for endometrial and cervical cancer patients

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Abstract

Background

Although the chemotherapy-induced depletion of circulating white blood cells (WBC) is well recognized, the impact of exclusive radiotherapy (RT) on the different subpopulations of WBC remains unexplored. This may be important for immunotherapy administrated in combination with radiation, especially in malignant tumors usually treated with RT or chemoradiotherapy (CRT), and characterized by a high mutational burden, such as endometrial (EC) or cervical cancer (CC). We aimed to evaluate the impact of RT and CRT on circulating WBC in uterine cancers and its correlation with survival.

Material and methods

A total of 202 consecutive patients with uterine cancers treated with RT or CRT between 2009 and 2016 in a large European center and with available basal and post-treatment blood tests were retrospectively evaluated. EC and CC patients were analyzed separately. The differences between pre- and post- treatment WBC mean values were evaluated independently in patients treated with CRT and exclusive RT. Two-sided T test for paired samples and Kaplan–Meier curves were applied for analysis (p value < 0.05, SPSS v.23).

Results

Among EC patients, 29 received CRT and 34 exclusive postoperative RT, while in CC cohort, 105 were treated with CRT and 34 with RT. In both cohorts, CRT affected significantly all WBC subtypes, whereas exclusive RT decreased only lymphocytes population (p = 0.000). Radiation-induced lymphopenia (RIL) had no impact on survival outcomes.

Conclusions

The selective depletion of lymphocytes after RT was significant in both EC and CC. Our results are of interest for further research on RIL and for design of immunotherapy-based clinical trials.

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References

  1. Venkatesulu BP, Mallick S, Lin SH, Krishnan S. A systematic review of the influence of radiation-induced lymphopenia on survival outcomes in solid tumors. Crit Rev Oncol Hematol. 2018;123:42–51. https://doi.org/10.1016/j.critrevonc.2018.01.003.

    Article  PubMed  Google Scholar 

  2. Grossman SA, Ellsworth S, Campian J, Wild AT, Herman JM, Laheru D, et al. Survival in patients with severe lymphopenia following treatment with radiation and chemotherapy for newly diagnosed solid tumors. J Natl Compr Canc Netw. 2015;13:1225–311.

    Article  CAS  Google Scholar 

  3. Yamagata S, Green GH. Radiation-induced immune changes in patients with cancer of the cervix. Br J Obstet Gynaecol. 1976;83(5):400–8.

    Article  CAS  Google Scholar 

  4. Standish LJ, Torkelson C, Hamill FA, et al. Immune defects in breast cancer patients after radiotherapy. J Soc Integr Oncol. 2008;6(3):110–21.

    PubMed  PubMed Central  Google Scholar 

  5. Schad MD, Dutta SW, Muller DM, et al. Radiation-related lymphopenia after pelvic nodal irradiation for prostate cancer. Adv Radiat Oncol. 2019;4(2):323–30. https://doi.org/10.1016/j.adro.2019.01.005. (eCollection 2019 Apr-Jun)

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ellsworth SG, Yalamanchali A, Zhang H, et al. Comprehensive analysis of the kinetics of radiation-induced lymphocyte loss in patients treated with external beam radiation therapy. Radiat Res. 2020;193(1):73–81. https://doi.org/10.1667/RR15367.1(Epub 2019 Nov 1).

    Article  CAS  PubMed  Google Scholar 

  7. Herzog T, Arguello D, Reddy S, et al. PD-1 and PD-L1 expression in 1599 gynecological malignancies: implications for immunotherapy. Gynecol Oncol. 2015;137:204–5.

    Article  Google Scholar 

  8. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590(Epub 2020 Jan 8).

    Article  PubMed  Google Scholar 

  9. Grywalska E, Sobstyl M, Putowski L, et al. Current possibilities of gynecologic cancer treatment with the use of immune checkpoint inhibitors. Int J Mol Sci. 2019;20(19):4705. https://doi.org/10.3390/ijms20194705.

    Article  CAS  PubMed Central  Google Scholar 

  10. Kagabu M, Nagasawa T, Fukagawa D, et al. Immunotherapy for uterine cervical cancer. Healthcare (Basel). 2019;7(3):108. https://doi.org/10.3390/healthcare7030108.

    Article  Google Scholar 

  11. Lynam S, Lugade AA, Odunsi K. Immunotherapy for gynecologic cancer: current applications and future directions. Clin Obstet Gynecol. 2019. https://doi.org/10.1097/GRF.0000000000000513.

    Article  Google Scholar 

  12. Rubinstein MM, Makker V. Optimizing immunotherapy for gynecologic cancers. Curr Opin Obstet Gynecol. 2020;32(1):1–8. https://doi.org/10.1097/GCO.0000000000000603.

    Article  PubMed  Google Scholar 

  13. Wu ES, Oduyebo T, Cobb LP, et al. Lymphopenia and its association with survival in patients with locally advanced cervical cancer. Gynecol Oncol. 2016;140(1):76–82. https://doi.org/10.1016/j.ygyno.2015.11.013(Epub 2015 Nov 11).

    Article  PubMed  Google Scholar 

  14. Diehl A, Yarchoan M, Hopkins A, Jaffee EM, Grossman SA. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget. 2017;8:114268.

    Article  Google Scholar 

  15. Zhuang Y, Yuan BY, Chen GW, et al. Association between circulating lymphocyte populations and outcome after stereotactic body radiation therapy in patients with hepatocellular carcinoma. Front Oncol. 2019;9:896. https://doi.org/10.3389/fonc.2019.00896(eCollection 2019).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tang C, Liao Z, Gomez D, et al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys. 2014;89(5):1084–91. https://doi.org/10.1016/j.ijrobp.2014.04.025.

    Article  PubMed  Google Scholar 

  17. van Rossum PSN, Deng W, Routman DM. Prediction of Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Development and Validation of a Pretreatment Nomogram. Pract Radiat Oncol. 2020;10(1):e16–e26. https://doi.org/10.1016/j.prro.2019.07.010(Epub 2019 Jul 29).

    Article  PubMed  Google Scholar 

  18. Chadha AS, Liu G, Chen HC, et al. Does unintentional splenic radiation predict outcomes after pancreatic cancer radiation therapy? Int J Radiat Oncol Biol Phys. 2017;97(2):323–32.

    Article  Google Scholar 

  19. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105:256–65.

    Article  CAS  Google Scholar 

  20. Ng SP, Bahig H, Jethanandani A, et al. Lymphopenia during radiotherapy in patients with oropharyngeal cancer. Radiother Oncol. 2020;145:95–100. https://doi.org/10.1016/j.radonc.2019.12.023.

    Article  CAS  PubMed  Google Scholar 

  21. Cho O, Oh YT, Chun M, et al. Radiation-related lymphopenia as a new prognostic factor in limited-stage small cell lung cancer. Tumour Biol. 2016;37(1):971–8. https://doi.org/10.1007/s13277-015-3888-y(Epub 2015 Aug 12).

    Article  PubMed  Google Scholar 

  22. Ho WJ, Yarchoan M. Hopkins A et al Association between pretreatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas. J Immunother Cancer. 2018;6(1):84. https://doi.org/10.1186/s40425-018-0395-x.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Soyano AE, Dholaria B, Marin-Acevedo JA, et al. Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung cancer patients treated with anti-PD-1 antibodies. J Immunother Cancer. 2018;6(1):129. https://doi.org/10.1186/s40425-018-0447-2.

    Article  PubMed  PubMed Central  Google Scholar 

  24. ** JY, Mereniuk T, Yalamanchali A, et al. A framework for modeling radiation induced lymphopenia in radiotherapy. Radiother Oncol. 2019;144:105–13. https://doi.org/10.1016/j.radonc.2019.11.014.

    Article  CAS  PubMed  Google Scholar 

  25. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18(7):895–903.

    Article  CAS  Google Scholar 

  26. Sun R, Champiat S, Dercle L, et al. Baseline lymphopenia should not be used as exclusion criteria in early clinical trials investigating immune checkpoint blockers (PD-1/PD-L1 inhibitors). Eur J Cancer. 2017;84:202–11. https://doi.org/10.1016/j.ejca.2017.07.033(Epub 2017 Aug 18).

    Article  CAS  PubMed  Google Scholar 

  27. Deng W, Xu C, Liu A, et al. The relationship of lymphocyte recovery and prognosis of esophageal cancer patients with severe radiation-induced lymphopenia after chemoradiation therapy. Radiother Oncol. 2019;133:9–15. https://doi.org/10.1016/j.radonc.2018.12.002(Epub 2019 Jan 11).

    Article  PubMed  Google Scholar 

  28. Tsuchiya T, Someya M, Takada Y, et al. Association between radiotherapy-induced alteration of programmed death ligand 1 and survival in patients with uterine cervical cancer undergoing preoperative radiotherapy. Strahlenther Onkol. 2020. https://doi.org/10.1007/s00066-019-01571-1.

    Article  PubMed  Google Scholar 

  29. Dovšak T, Ihan A, Didanovič V, et al. Effect of surgery and radiotherapy on complete blood count, lymphocyte subsets and inflammatory response in patients with advanced oral cancer. BMC Cancer. 2018;18(1):235. https://doi.org/10.1186/s12885-018-4136-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Mrs. Rosa Gimenez for her assistance.

Funding

This study received no funding.

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Authors and Affiliations

  1. Radiotherapy Department, Gustave Roussy Cancer Campus, Villejuif, France

    K. Holub

  2. Radiation Oncology Department, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain

    K. Holub, A. Vargas & A. Biete

  3. Department of Radiation Oncology, Clínica Instituto de Radiomedicina (IRAM), Santiago de Chile, Chile

    A. Vargas

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Correspondence to K. Holub.

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All procedures performed in our studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Some preliminary results of this study were accepted for the presentation at the 39th ESTRO Annual Meeting in 2020 in Vienna.

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Holub, K., Vargas, A. & Biete, A. Radiation-induced lymphopenia: the main aspects to consider in immunotherapy trials for endometrial and cervical cancer patients. Clin Transl Oncol 22, 2040–2048 (2020). https://doi.org/10.1007/s12094-020-02345-3

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  • DOI: https://doi.org/10.1007/s12094-020-02345-3

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